Field of the Disclosure
The present disclosure relates generally to pharmaceutical compositions, and more particularly, to transdermal pharmaceutical compositions including clomiphene-like selective estrogen receptor modulators (C-SERMs) for testosterone deficiency.
Background Information
Male testosterone deficiency is a syndrome associated with hormonal profile changes that negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Further, testosterone deficiency has been shown to be related to low quality of erections, loss of libido, osteoporosis, weight gain, muscle weakness, decreased lean body mass, diabetes mellitus, and cognitive changes. The decrease in serum testosterone may be due to primary testicular failure and/or dysfunction of the hypothalamic-pituitary axis. This testosterone deficiency in aging males is associated with increased body weight and adipose tissue, and changes in estrogen levels due to peripheral conversion of testosterone to estradiol. The negative feedback mechanism from excess estradiol results in a paradoxically low luteinizing hormone (LH) secretion from the pituitary gland despite a physiologically low testosterone level. Unfortunately, low LH secretion results in a decrease in testosterone production.
Currently, the most common treatment for symptomatic male testosterone deficiency is testosterone replacement therapy employing various oral and injectable delivery methods. These methods typically involve high doses of testosterone. The main purpose of the testosterone replacement therapy is to achieve normal range of testosterone serum levels.
Current oral therapy of testosterone lacks effectiveness because testosterone is metabolized extensively during the first passage of the liver before reaching the systemic blood circulation (e.g., the first-pass effect). Intramuscular injections of testosterone are widely used, but severe drawbacks for this form of treatment include local pain, soreness, minor swelling, and the unphysiologically high levels of testosterone in the body during the first days/weeks after injection. Local pain is attributed to the large volumes of testosterone injected at a specific injection site. Other drawbacks of intramuscular injections include the need for required assistance of health care professionals thereby making injections inconvenient and expensive.
Additionally, testosterone replacement therapy can be associated with side effects, such as gynecomastia, nipple tenderness, and the like. Further, long term testosterone replacement therapy will cause testicular atrophy and decline in sperm counts due to suppression of the hypothalamic-pituitary-gonadal axis via a negative feedback mechanism. Low levels of gonadotropin releasing hormone (GnRH) further decrease production of LH and follicle stimulating hormone (FSH) by the pituitary gland. The low LH levels translate to low testosterone production by the Leydig cells in the testes. The reduction in FSH could result in suppression of spermatogenesis. Physiologic inhibition of pituitary gonadotropin secretion in men by testosterone is mainly mediated by aromatization to estrogen, which inhibits hypothalamic secretion of GnRH. Therefore, there is a need for a testosterone replacement therapy that does not include the aforementioned side-effects.